The research by scientists from Newcastle University, the University of Munich, and the University of Liverpool has been published in the American Journal of Human Genetics.

The starting point for their discovery was a family in which two of six children had been living with delayed motor development and muscle weakness since birth.

In addition to skeletal muscles, eyes and brain seemed to be affected as well. Both patients developed early-onset cataracts and had mild mental difficulties. The scientists analysed the whole exome of the patients, that is to say all regions of the DNA that encode proteins.

Gene mutation

This analysis resulted in a suspicious variant in the gene, INPP5K, which appeared to be related to the manifestation of the disease. Definite proof came from genetic studies involving further unrelated patients with the same disorder. Together with colleagues at home and abroad, the research team came across INPP5K mutations in seven additional families.

In order to understand the mechanism of the disorder, the researchers investigated the function of INPP5K in zebrafish larvae. The loss of INPP5K caused defective development of skeletal muscles and eyes, replicating essential features of the human disease.

The INPP5K gene provides the blueprint for making an enzyme that controls the turnover of phosphoinositides, small lipids that are involved in the regulation of a variety of cell and organ functions. Further experiments showed that most disease-related INPP5K mutations resulted in strongly impaired enzyme function.

The association between abnormal phosphoinositide metabolism and hereditary human diseases had already been demonstrated in earlier studies. However, mutations did not affect the INPP5K gene but were found in genes for other phosphoinositide-metabolizing enzymes. 

Quicker diagnosis

Hanns Lochmuller, professor of experimental myology at the Institute of Genetic Medicine, led the Newcastle University team researching the gene mutation.

He said: “We have discovered this new gene through international collaboration and data sharing of genomics data. This enables clinicians in the UK and elsewhere to diagnose the condition rapidly and support affected children and their families.”

Reference

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

The American Journal of Human Genetics. Doi: http://dx.doi.org/10.1016/j.ajhg.2017.01.024